The general hypothesis of this research program is that biological mechanisms responsible for different forms of inherited glaucoma represent different processes that culminate in optic nerve degeneration. Elucidating each mechanism will produce a composite picture of the complex pathophysiology of this disease. The primary objective of this proposal is to characterize genetic defects responsible for inherited glaucoma, and to determine the relationships between specific mutations and clinical phenotype. In addition to providing insight into disease related molecular pathology, this information will be the basis of new treatment and diagnostic modalities. Identifying genes and gene projects that contribute to the disease process will be the first step toward the development of novel treatment based on specific disease mechanisms. The correlation of gene defects with clinical phenotypes will provide the fundamental knowledge needed to devise DNA-based diagnostic and prognostic tests. Screening different populations of glaucoma patients will illustrate the range of phenotypic expression of mutant genes and will indicate mutations that may contribute to the pathogenesis of more complex forms of the disease. During the previous grant cycle, a genome wide scan for juvenile open angle glaucoma (JOAG) was completed identifying two new JOAG loci, the genetic interval of the 7q36 PDS locus has been reduced to 5cM, and a second locus for pigment dispersion syndrome has been identified, the genetic interval for the RIEG2 locus has been reduced to 7cM and candidate genes have been identified and screened, and genotype/phenotype studies have been completed on patients with abnormalities in the TIGR/Myocilin gene, the CYP1B1 gene and the RIEG1 gene (PITX2). During the next grant period, we plan to achieve the following specific aims: 1) Refine the newly identified loci for juvenile open angle glaucoma (JOAG) and identify and screen candidate genes. 2) Screen candidate genes located in the pigment dispersion (PDS) regions located on 7q35 and 18q22. 3) Screen candidate genes located in the RIEG2 region on chromosome 13q14. 4) Correlate mutations in genes known to cause glaucoma with clinical phenotypes.